This research proposal reflects our interest in the areas of new reaction methodology development, applications to the synthesis of biologically active natural products, and their mechanism of action. We intend to develop and further refine synthetic methodologies for the synthesis of bioactive enamides, as well as related N-acylheminal natural products. We plan to study the chemical reactivity and biological activity of these molecules via specific biological collaborations. In addition to methodology development, the synthesis of structurally complex and biologically active natural products will be pursued: We intend to complete the synthesis of the salicylate macrolide lobatamide C in order to assign the absolute stereochemistry at unknown stereogenic centers, evaluate the biological activity of synthetic intermediates, and prepare both stereochemical analogues and photoaffinity probes. We intend to synthesize the cytotoxic peptide enamide natural products chondriamide C and terpeptin and diverse analogues using chemical modification of C-terminal peptides. We intend to pursue the asymmetric synthesis of novel antitumor and cell-cycle inhibitory macrolide oximidine I. We will pursue the asymmetric synthesis of the antitumor compound zampanolide whose natural resource has been depleted.